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. 2022 Aug 10;14:979869. doi: 10.3389/fnagi.2022.979869

FIGURE 1.

FIGURE 1

A schematic illustration of two major pathways of mitophagy in mammalian cells. (1) Ubiquitin (Ub)-mediated mitophagy pathways. PINK1 accumulates on the OMM of depolarized mitochondria and undergoes auto-phosphorylation. (a) PINK1 then recruits cytosolic Parkin translocation to the OMM and activates this E3 Ub ligase by phosphorylation, which ubiquitinates several OMM proteins such as mitofusin, VDAC and Miro. PINK1 also directly phosphorylates the preexisting Ub on the OMM. Ub is also able to recruit and activate Parkin. The actions of PINK1 and Parkin cooperatively lead to the polyUb process of damaged mitochondria, which can be recognized by mitophagy adaptors (p62, OPTN, NDP52, NBR1, TAX1BP1) to mediate mitochondria sequestrated by autophagosomes. (b) Apart from Parkin, other E3 ubiquitin ligases [ARIH1, seven in absentia homolog (SIAH)-1 and RNF34, etc.] have been reported to mediate mitophagy in a PINK1-dependent manner. (2) Receptor-mediated mitophagy. OMM proteins including FUNDC1, AMBRA1, BNIP3L/Nix, BNIP3 serve as mitophagy receptors under specific conditions (hypoxia, erythrocyte maturation, and toxin exposure). These receptors directly bind to LC3 via the LIR motif. Additionally, a few IMM proteins such as cardiolipin and prohibitin 2 can translocate to the OMM under certain conditions, where they also serve as mitophagy receptors and promote mitophagy through their LIR to interact with LC3 on the autophagosomes. OMM, outer mitochondrial membrane; IMM, inter mitochondrial membrane; LIR, LC3-interacting region.